1-benzyl-4- or 5-pyrrolidinomethyl-pyrrolidin-2-ones and nootropic method of use thereof

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is hydrogen or alkyl of 1 to 4 carbon atoms; 
     R 2  is 2-, 3- or 4-pyridyl, phenyl or mono- or di- substituted phenyl, where the substituents are each individually alkoxy of 1 to 2 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl, alkyl or 1 to 4 carbon atoms, hydroxyl or nitro; and 
     R 3  and R 4  are each independently hydrogen or alkyl of 1 to 4 carbon atoms; or 
     R 3  and R 4 , together with each other and the nitrogen atom to which they are attached, form an unsubstituted or methyl-substituted, saturated 5- or 6-membered heterocycle which may contain an additional oxygen or nitrogen heteroatom, or form an imidazole ring; 
     where the aminomethyl substituent is attached to the 4- or 5-position or the pyrrolidine ring, and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as the salts are useful as nootropics and antihypoxics.

This is a continuation application of Ser. No. 199,291 filed May 26,1988, now U.S. Pat. No. 9,833,190, which is a divisional of Ser. No.878,828 filed Jun. 26, 1986, now U.S. Pat. No. 4,767,759 which is inturn a CIP of Ser. No. 657,219 filed Oct. 2, 1984 abandoned.

This invention relates to novel 1-benzy- 4 or5-amino-methyl-pyrrolidin-2-ones ones and non-toxic acid addition saltsthereof, to methods of preparing these compounds, to pharmaceuticalcompositions containing them as active ingredients, and to a method ofusing them as nootropics and antihypoxics.

THE PRIOR ART Japanese patent application No. 78 44 559 (JP-A-78 44 559)discloses, inter alia,N-[(S)-α-methylbenzyl]-6-oxo-2-(S)pyrrolidyl-methylamine of the formula##STR2## as an intermediate product and does not ascribe anypharmacological properties thereto.

Structurally related nootropics, such as1-carbamoyl-methyl-pyrrolidin-2-one one (piracetam),1-(p-methoxybenzoyl)-pyrrolidine-2-one (aniracetam) and1-carbamoylmethyl-4-hydroxy-pyrrolidine-2-one one (oxiracetam) aredisclosed in the literature;

Drug Development Res. 2, 464 (1982, and see B.J.R. Nicolaus, P.L.Paytasch, J.Amer.Chem.Soc. 72, 1415 (1950).

THE INVENTION More particularly, the present invention relates to anovel class of compounds represented by the formula ##STR3## wherein R₁is hydrogen or alkyl of 1 to 4 carbon atoms;

R₂ is 2-, 3- or 4-pyridyl, phenyl or mono- or di

substituted phenyl, where the substituents are each individually alkoxyof 1 to 2 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl,alkyl of 1 to 4 carbon atoms, hydroxyl or nitro; and

R₃ and R₄, which may be identical to or different from each other, areeach independently hydrogen or alkyl of 1 to 4 carbon atoms; or

R₃ and R₄, together with each other and the nitrogen atom to which theyare attached, form an unsubstituted or methyl-substituted, saturated 5-or 6-membered heterocycle which may contain an additional oxygen ornitrogen heteroatom, or form an imidazole ring;

here the aminomethyl substituent is attached to the 4- or 5-position ofthe pyrrolidine ring, provided, however, that when the aminomethylsubstituent is attached to the 5-position of the pyrrolidine ring, R₁ ismethyl and R₃ and R₄ are hydrogen, R₂ is other than phenyl, andnon-toxic, pharmacologically acceptable acid addition salts thereof.

A preferred subgenus thereunder is constituted by those compounds of theformula I

where

R₁ is hydrogen;

R₂ is phenyl or o- or p-monosubstituted phenyl, where the substituent isfluorine, chlorine, methyl or methoxy; and

R₃ and R₄ are each independently hydro9en, methyl or ethyl;

and non-toxic, pharmacologically acceptable acid addition salts

The compounds embraced by formula I are basic and therefore formaddition salts with inorganic or organic acids.

Examples of non-toxic, pharmacologically acceptable acid addition saltsare those formed with hydrohalic acid, sulfuric, phosphoric,aminosulfonic, formic, acetic, propionic, lactic, glycolic, gluconic,maleic, fumaric, succinic, tartaric, benzoic, salicylic, citric,ascorbic, p-toluenesulfonic, oxyethane sulfonic acid or the like.

The compounds embraced by formula I may be prepared by the followingmethods:

Method A

For the preparation of a compound of the formula I wherein R₃ and/or R₄are other than hydrogen, by reacting a 4- or5-hydroxymethyl-pyrrolidin-2-one of the formula ##STR4## wherein R₁ andR₂ have the meanings previously defined, with a thionyl halide, aphosphorus halide, a tosyl halide or a mesyl halide to form anintermediate compound of the formula ##STR5## wherein R₁ and R₂ have themeanings previously defined, and

X is halogen, tosyloxy or mesyloxy, and subsequently reacting saidintermediate compound with a primary or secondary amine of the formula##STR6## wherein R₃ and R₄ have the meanings previously defined.

A compound of general formula II is converted either with a thionyl orphosphorus halide into the corresponding 4-halomethyl compound or with atosyl or mesyl halide into the corresponding 4-tosyl or 4-mesyl ester.The reaction is preferably carried out in an inert organic solvent suchas chloroform, methylene chloride, tetrahydrofuran or dimethylformamideat temperatures between room temperature and the boiling point of thesolvent which is used. In the case of esterification, a tertiary organicbase such as triethylamine or pyridine is preferably added. The4-halomethyl compounds produced as intermediates or the 4-tosyl or4-mesyl esters may be isolated or may be reacted further in situ. Whenthey are subsequently treated with a primary or secondary amine, thecorresponding end products of the formula I are obtained. The reactionmay be carried out in tetrahydrofuran, dioxane, acetonitrile or,preferably, in dimethylformamide at a temperature between about 50 and150° C., the individual reaction conditions depend on the basicity andthe boiling point of the amine. The reaction may also be carried outwithout the use of a solvent in an excess of the amine. In the case oflow-boiling-point amines, the reaction must be carried out in anautoclave under certain circumstances.

The end products of the formula I with a free amino group are preferablysynthesized by reacting a compound of the formula III with phthalimideor an alkali metal salt of phthalimide, and cleaving the4-phthalimidomethyl compound thus obtained with hydrazine.

The reaction with phthalimide is carried out in an inert organic solventsuch as acetonitrile or an alcohol, or preferably in dimethylformamide,at elevated temperatures up to the boiling point of the reactionmixture. The 4-phtalimidomethyl compound may be isolated or reactedfurther in situ; the phtalimide group may be split off with hydrazine.For this purpose, alcohols, ttrahydrofuran, dioxane, dimethylformamideor mixtures of alcohols and dimethylformamide may be used as solvents.Frequently, the reaction starts even at room temperature; if desired, ahigher temperature may be used in order to speed up the reaction.

Method B

Another method of preparing the nor compound comprises hydrogenating acompound of the formula ##STR7## wherein R₁ and R₂ have the meaningspreviously defined, and

Y is --CH₂ N₃ or --CN.

The hydrogenation is preferably carried out with Raney nickel inmethanol or with palladium in methanol/water, and possibly with theaddition of ammonia in the case of the hydrogenation of the nitrile.

An azide of the formula V (Y=--CH₂ Nhd 3) is obtained by reacting acompound of the formula III wherein X is halogen, or mesyl, with sodiumazide in an inert organic solvent, for instance an alcohol or an ethersuch as tetrahydrofuran or dioxane.

A nitrile of the formula V(Y=--CN) may be prepare for example, byreacting a solution of a carboxylic acid of the formula VI ##STR8##wherein R₁ and R₂ have the meanings previously defined, in acetonitrilewith chlorosulfonyl isocyanate and subsequently with triethylamine, orby dehydration of the corresponding carboxylic acid amide with POCl₃,for example (cf. H. Vorbruggen, Tetrahedron Letters 1968, pages1631-1634).

The novel compounds of the formula I have a center of asymmetry andtherefore occur as racemates. These racemates may be converted in theusual way, for instance by salt formation with optically active acids,into the corresponding diastereoisomers, which can then be convertedinto the optically active end products.

If desired, the alcohols of the formula II may be converted by esterformation with optically active acids into the corresponding mixtures ofdiastereoisomers which can then be resolved into the individualdiastereoisomers by conventional methods, for instance by columnchromatography or fractional crystallization. After hydrolysis of theseesters, the enantiomeric alcohols are obtained from which thecorrespondin9 amines are prepared by method A or B.

Starting from the enantiomeric nor compounds, the correspondingoptically pure diethyl compounds may .be obtained by reductivealkylation, for example with acetaldehyde/H_(2/) catalyst, or thecorresponding optically pure dimethyl compounds may be obtained withformaldehyde/formic acid.

The starting materials for methods A and B described above are known ormay be obtained by known methods. Thus, a pyrrolidinone carboxylic acidof the formula VI is prepared by reacting equimolar quantities ofitaconic acid and a corresponding amine. The starting compounds of theformula II can be obtained from the acid via the ester by selectivereduction with a complex alkali metal borohydride (cf. GermanOffenlegungs schrift No. 3,326,724).

In the case of the 5-aminoalkyl compounds, the commercially available5-pyrrolidinone-carboxylic acids may be used as starting materials;these are esterified, alkylated at the nitrogen with an optionallysubstituted benzyl halide, and reacted further as described above.

The following end products of the formula I may be obtained, forexample, using the methods described above, possibly in the form oftheir acid addition salts and possibly in the form of the pureenantiomers:

1-Benzyl-4-aminomethyl-pyrrolidin-2-one,

1-(4-Methoxybenzyl)-4-aminomethyl-pyrrolidin-2-one,

1-(3,4-Dimethoxybenzyl)-4-aminomethyl-pyrrolidin-2one,

1-(4-Methylbenzyl)-4-aminomethyl-pyrrolidin-2one,

1-(4-Fluorobenzyl)-4-aminomethyl-pyrrolidin-2-pne.

1-(4-Chlorobenzyl)-4-aminomethyl-pyrrolidin-2-one,

1-(3-Trifluoromethylbenzyl)-4-aminomethyl-pyrrolidin-2-one,

1-(4-Pyridylmethyl)-4-aminomethyl-pyrrolidin-2-one,

1-(α-Methylbenzyl)-4-aminomethyl-pyrrolidin-2-one,

1-Benzyl-4-piperidinomethyl-pyrrolidin-2-one,

11-(4-Fluorobenzyl)-4-morpholino-methyl-pyrrolidin-2-one,

11-Benzyl-4-(N-methylpiperazino)-methyl-pyrrolidin-2-one,

11-Benzyl4-imidazol-1-yl-methyl-pyrrolidin-2-one,

11-Benzyl-4-methylaminomethyl-pyrrolidin-2-one,

11-(p-Fluorobenzyl)-4-dimethylaminomethyl-pyrrolidin-2-one,

11-Benzyl-4-diethylaminomethyl-pyrrolidin-2-one,

11-(4-Nitrobenzyl)-4-aminomethyl-pyrrolidin-2-one,

11-(4-Hydroxybenzyl)-4-aminomethyl-pyrrolidin-2-one,

11-(o-Chlorobenzyl)-4-aminomethyl-pyrrolidin-2-one,

11-(o-Chlorobenzyl)-4-diethylaminomethyl-pyrrolidin-2-one,

11-Benzyl-4-isopropylaminomethyl-pyrrolidin-2-one,

1-(p-Methylbenzyl)-4-diethylaminomethyl-pyrrolidin-2-one,

1-Benzyl-5-dimethylaminomethyl-pyrrolidin-2-one,

1-Benzyl-5-diethylaminomethyl-pyrrolidin-2-one,

1-Benzyl-5-morpholinomethyl-pyrrolidin-2-one,

1-Benzyl-5-(4-methylpiperazino)-methyl-pyrrolidin-2-one,

1-Benzyl-5-pyrrolidinomethyl-pyrro

1-(4-Methylbenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one,

1-(4-Methylbenzyl)-5-diethylaminomethyl-pyrrolidin-2-one,

1-(p-Chlorobenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one,

1-(p-Chlorobenzyl)-5-diethylaminomethyl-pyrrolidin-2-one,

1-(3,4-Dichlorobenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one,

1-(3,4-Dichlorobenzyl)-5-diethylaminomethyl-pyrrolidin-2-one,

11-(p-Methoxybenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one,

11-(p-Methoxybenzyl)-5-diethylaminomethyl-pyrrolidin-2-one,

11-Benzyl-5-aminomethyl-pyrrolidin-2-one.

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below.

EXAMPLE 1 1-10 1-Benzyl-4-aminomethyl-pyrrolidin-2-one

A solution of 54 g (0.16 mol) of 4-phthalimidomethyl-1-benzyl-pyrrolidin-2one in 1.3 liters of ethyl alcohol was stirred, afterthe addition of 32 g of hydrazine hydrate, for 4 hours at roomtemperature. The precipitate (phthalic acid hydrazide) wassuction-filtered off, and the filtrate was evaporated. 500 ml ofmethylene chloride was added to the residue, and the mixture wasextracted three times with 100 ml of water. The organic phase was driedand evaporated. The residue was dissolved in 500 ml of methanol, and 20g (0.17 mol) of solid fumaric acid were added in batches to the boilingmixture while stirring. Upon cooling, colorless crystals precipitatedwhich were suction-filtered off and then washed with methanol and ether.Yield: 20-25 g (48-60% of theory), m.p. 190-192° C. The compoundcontained 1/2 mol of fumaric acid.

The starting material was obtained-as.follows:

(a) 94 g (0.46 mol) of 1-benzyl-4-hydroxymethyl-pyrrolidin-2-one onewere stirred with 700 ml of methylene chloride and 40 ml (0.54 mol) ofthionylchloride for 25 hours while refluxing, and the reaction mixturewas then neutralized with dilute ammonia while cooling. Afterseparation, drying and evaporation, 85-90 g of a dark oil were leftbehind, which is used directly for further reaction.

(b) A mixture of 43.5 g (0.195 mol) of crude1-benzyl-4-chloromethyl-pyrrolidin-2-one, 36 g (0.195 mol) ofphthalimide potassium and 700 ml of dimethylformamide was refluxed fortwo hours. The reaction mixture was then evaporated in vacuo, and theresidue was taken up in methylene chloride. The solution was extractedseveral times with water, the organic phase was dried, and afterchromatography on SiO₂ 45 g (70% of theory) of the phthalimido compoundwere obtained, m.p. 108-109° C.

EXAMPLE 2 1-Benzyl-4-aminomethyl-pyrrolidin-2-one

(a) 58 g (0.29 mol) of 1-benzyl-4-cyano-pyrrolidin-2one were dissolvedin methanol and catalytically hydrogenated with the addition of liquidammonia over Raney nickel. After evaporation of the reaction solutionthe mixture was dissolved in methanol, the residual catalyst wasfiltered off, and after the filtrate had been heated to about 50° C. itwas mixed with 17 g of fumaric acid. The fumaric acid briefly went intosolution upon stirring, and then crystallization of the 1-benzyl-4-aminomethyl-pyrrolidine-2one one fumarate began. Yield: 68 g (91% oftheory). M.p. 192-194° C.

(b) The cyano compound was obtained with a 96% yield in the form of anoil from the corresponding amide. M.p. 162-166° C., by dehydration withPOCl₃ in dimethylformamide at about 60° C.

EXAMPLE 2 Racemate cleavage of 1-benzyl-4-aminomethyl-pyrrolidin-2-one

(a) 24.0 g (0.117 mol) of 1-benzyl-4.aminomethyl-pyrrolidin-2-one onewere dissolved in 200 ml of hot methanol, and 17 6 g (0.117 mol) ofL(+)-tartaric acid were also dissolved in 200 ml of hot methanol. Thetwo solutions were combined and cooled to room temperature withstirring, whereupon the salt crystallized out. The crystals weresuction-filtered off while cold, washed with cold methanol and dried.

0 g of 4-aminomethyl-1-benzyl-pyrrolidin-2-one Yield: 18.0 g of4-aminomethyl-1benzyl-pyrrolidin-2-one tartrate. M.p. 204-206° C. (frommethanol, α_(D) =+6.3° (c=1.0; water).

(b) In order to convert the tartrate into the base, the tartrate wasdissolved in a cold mixture of 20 ml of water and 10 ml of concentratedsodium hydroxide and the solution was extracted three times Withmethylene chloride. The combined methylene chloride phases were driedover MgSO₄, and the solvent was evaporated in vacuo, yielding(-)-4-aminomethyl-1-benzyl-pyrrolidin-2-one, α_(D) =-8.4° (c=1.0;water).

(c) The mother liquors obtained in the work-up described in (a) wereevaporated in vacuo. 38.0 g of the tartrate were obtained, which wastaken up in a cold mixture of 140 ml of water and 50 ml of concentratedsodium hydroxide, and the solution was extracted three times withmethylene chloride. The combined methylene chloride phases were driedover MgSO₄, and the solvent was evaporated in vacuo. 19.3 g of base wereobtained, which was converted into the corresponding tartrate withD-(-)-tartaric acid as described in (a). Yield 19.0 g. M.p. 204-205° C.

(d) The conversion of the tartrate into the base was carried out asdescribed in (b). 5.7 g of (+)-4-aminomethyl1-benzyl-pyrrolidin-2-onewith a rotation α_(D=+) 8.4° (c =1.0; water) were obtained.

EXAMPLE 4 (-)-1-Benzyl-4-dimethylaminomethyl-pyrrolidin-2-one

4 0 g (0.02 mol) of (-)-1-benzyl-4-aminomethyl-pyrrolidin 2-one and 5.4g of 85% formic acid were mixed with 4.8 ml of formalin solution andstirred overnight at 100° C (oil bath). Then the axcess acid wasdistilled off in vacuo, the residue was taken up in water, and thesolution was made alkaline with concentrated sodium hydroxide and thenextracted three times with methylene chloride. The combined methylenechloride phases were washed with water and dried over sodium sulfate,the solvent was evaporated in vacuo, and the residue was filteredthrough an SiO₂ column (eluant: methylene chloride:methanol=97:3). Theuniform fraction was evaporated in vacuo. The title compound wasobtained with a yield of 3.5 g (in the form of an oil).

α_(D) =-7.6° (c=1.0; methanol),

α_(D) =-16.8° (c=1.0; water).

Analogously, 6.1 g of(+)-1-benzyl-4-dimethylamino-methyl-pyrrolidin-2-one were obtained,α_(D) =+7.9° (c =1.0; methanol), from 5.8 g (0.028 mol) of(+)-1-benzyl-4-aminomethyl-pyrrolidin-2one, 7.9 g of 85% formic acid and7 ml of formalin solution.

EXAMPLE 5 1-4-diethylaminomethyl-pyrrolidin-2-one

A mixture of 14 g (0.06 mol) of crude1-benzyl-4-chloro-methyl-pyrrolidin-2-one, prepared as in Example 1(a),10 g of diethylamine and 50 ml of dimethylformamide was stirred orshaken for 2 hours at 150° C. in an autoclave. The reaction mixture wasevaporated to dryness in vacuo, the residue was taken up in methylenechloride, and the solution was washed first with water and finally thetitle compound was extracted twice with 25 ml of 2 N HCl. The aqueousphase was separated, made alkaline with sodium hydroxide and the organicbase was extracted with methylene chloride. The methylene chloride phasewas evaporated, and the residue was distilled in vacuo. Yield: 10 g (61%of theory), bp₀ 05 =155-158° C.

EXAMPLE 6 (-)-1-Benzyl-4-diethylaminomethyl-pyrrolidin-2-one

A mixture of 11.5 g (0.056 mol) of (-)-1-benzyl-4-aminomethyl-pyrrolidin-2-one, 130 ml of water, 13 g of acetaldehyde, 5.8 mlof concentrated hydrochloric acid and 6.5 g of 20% palladium-on-charcoalwas hydrogenated for 51/4hours at 5 bar and at 25° C. The reactionmixture was filtered, the filtrate was evaporated, the residue was takenup in 30 ml of water, and the solution was extracted with methylenechloride. The aqueous hydrochloric acid solution was made alkaline andthen extracted with methylene chloride. By distillation of the combinedextracts in a bulbed tube, 11.2 g (76.4% of theory) of the titlecompound were obtained, α_(D) =-9.4 (c=1.0; methanol).

Analogously, by hydrogenating a mixture of 8.4 g (0.041 mol) of(+)-1-benzyl-4-aminomethyl-pyrrolidin-2-one, 95 ml of water, 9.5aceta1dehyde, 4.2 ml of concentrated hydrochloric acid and 4.7 g of 20%Pd/C, (+)-1-benzyl-4-diethylaminomethyl-pyrrolidin-2one, α_(D) =+9.4(c=1.0; methanol), was obtained.

Example 71-(4-Fluoro-benzyl}-4-N-methylpiperazinylmethyl-pyrrolidin-2one

(a) 24 g (0.11 mol) of 1-(4-fluorobenzyl)-4-hydroxymethyl-pyrrolidin-2-one were refluxed with 10 ml (0.14 mol) of thionylchloride in 200 ml of methylene chloride first for 10 hours and then,after the addition of another 10 ml of thionyl chloride, for 6 hoursmore. While cooling with ice, the reaction mixture was neutralized withammonia, and after the organic phase was separated, it was dried andevaporated. 23 g (92% of theory) of a reddish-brown oil remained, whichwas used without any further purification.

(b) 5 g (0.002 mol) of the above oil were refluxed for 1 to 2 hours with4.4 g (0.04 mol) of 1-methyl-piperazine in 30 ml of dimethylformamide.The dimethylformamide was then substantially distilled off in vacuo, theresidue was taken up in methylene chloride, the solution was washed withwater, and the organic phase was dried and evaporated. The residue waschromatographed on SiO₂ with methylene chloride/methanol 95:5 as theeluant. The main fraction was evaporated, and the residue (5 g) wasdissolved in 30 ml of methanol. 2.8 g of fumaric acid were added to thissolution. 5.2 g (48% of theory) of the fumarate of the title compoundwere precipitated in crystalline form.

M p. 179-180° C.

EXAMPLE 8 1-(4-Fluorobenzyl)-4-morpholinomethyl-pyrrolidin-2-one

(a) A solution of 8.9 g (0.04 mol) of.1-(4-fluoro-benzyl-4-hydroxyl-pyrrolidin-2-one in 100 ml of absolute methylene chloride and4.8 g of pyridine was mixed with 6.9 g (0.06 mol) of methanesulfonicacid chloride. The mixture was refluxed for 2.5 hours and then cooledand extracted with dilute ammonia and water. The organic phase was driedand evaporated. 11 g (93% of theory) of crude ester, m.p. 84-86° C.,were obtained.

(b) 6.7 g (0.023 mol) of the ester obtained in (a) and 2.6 g (0.03 mol)of morpholine were refluxed for 2 hours in 20 ml of dioxane. The solventwas then evaporated in vacuo, the residue was taken up in methylenechloride, and the solution was extracted with 50 ml of 2 N hydrochloricacid. The aqueous extracts were made alkaline with ammonia, and the oilybase which separated out was extracted with methylene chloride. Themethylene chloride phase was dried and evaporated. The residue (4.2 g)was taken up in 30 ml of methanol, and 1.2 g of fumaric acid were addedto the warm methanolic solution. After cooling, the fumarate of thetitle compound precipitated in crystalline form. Yield 7 g =57% oftheory of colorless crystals, m.p. 175-176° C.

EXAMPLE 9 1-(4-Fluorobenzyl)-4-aminomethyl-pyrrolidin-2-one

(a) 4.0 g (0.013 mol) of the mesyl ester prepared in Example 7 wererefluxed for 30 minutes with 2.8 g (0.015 mol) of phthalimide potassiumin 5(ml of dimethylformamide. reaction mixture was evaporated in vacuo,and the residue was taken up in methylene chloride, the solution waswashed with water, and the organic phase was dried and again evaporated.The residue was triturated with ether and yielded 3.6 g (78% of theory)of light grey crystals, m.p. 124-125° C.

(b) 3.5 g (0.1 mol) of the phthalimide compound obtained in (a) werestirred with 5.5 g of hydrazine hydrate in 200 ml of alcohol for 4 hoursat room temperature. The mixture was worked up as described inExample 1. 2.5 g (89% of theory) of the fumarate of the title compound,m.p. 214-215° C, were obtained.

The title compound may also be obtained by dissolving 5 g (16 mmols) ofthe mesyl ester (see Example 7) in 100 ml of dimethylformamide and,after the addition of 1.3 g of sodium azide, heating the mixture to 100°C for 2 hours, hydrogenating the oil which is obtained with Raney nickelin methanol, and converting the base into the fumarate as describedabove. Yield: 4.2 g (90% of theory).

Using procedures analogous to those described in the preceding examples,the compounds of the formula I shown in the following table were alsoprepared:

                                      TABLE 1                                     __________________________________________________________________________     ##STR9##                                                                     Example                                                                       No.  R          R.sub.1                                                                           R.sub.2    M.p.                                                                              °C./Bp.°C                    __________________________________________________________________________    10   NH.sub.2   H                                                                                  ##STR10## Mp. 215-216 (Fumarate)                         11   NH.sub.2   H                                                                                  ##STR11## Mp. 187-189 (Fumarate)                         12   NH.sub.2   H                                                                                  ##STR12## Mp. 225-226 (Fumarate)                         13   NH.sub.2   H                                                                                  ##STR13## Mp. 189 191 (Fumarate)                         14   NH.sub.2   H                                                                                  ##STR14## Mp. 168-169 (Fumarate)                         15   NH.sub.2   H                                                                                  ##STR15## Mp. 179- 181 (Fumarate)                        16   NH.sub.2   CH.sub.3                                                                           ##STR16## Mp. 167-168 (Fumarate)                         17                                                                                  ##STR17## H                                                                                  ##STR18## Mp. Bp.sub.0.05                                                                   58-60 180 (Base)                           18                                                                                  ##STR19## H                                                                                  ##STR20## Mp. 190-192 (Fumarate)                         19                                                                                  ##STR21## H                                                                                  ##STR22## Mp..sub.0.05                                                                      230 (Base)                                 20   HNCH.sub.3 H                                                                                  ##STR23## Bp..sub.0.05                                                                      180 (Base)                                 21   NH.sub.2   H                                                                                  ##STR24## Mp. 179-180 (Fumarate)                         22                                                                                  ##STR25## H                                                                                  ##STR26## Bp..sub.0.05                                                                      156 (Base)                                 23   NHCH(CH.sub.3).sub.2                                                                     H                                                                                  ##STR27## Bp..sub.0.05                                                                      175 (Base)                                 24                                                                                  ##STR28## H                                                                                  ##STR29## Bp..sub.0.05                                                                      175 (Base)                                 __________________________________________________________________________

Example 25

1-Benzyl-5-dimethylaminomethyl-pyrrolidin-2-one

(.)a A solution of 10.26 g (0.05 mol) of1-benzyl-5-hydroxymethyl-pyrrolidine-2-one one (m.p. 76-77° C.) and 5.6g (0.055 mol) of triethylamine in 80 ml of methylene chloride was mixedwith a solution of 6.3 g (0.055 mol) of methanesulfonic acid chloride in20 ml of methylene chloride. The reaction mixture was then refluxed forone hour, and after cooling it was extracted with water. The organicphase was dried over anhydrous sodium sulfate and then evaporated in arotary evaporator. 14.1 g (yellow oil) of crude1-benzyl-5-hydroxymethyl-pyrrolidin-2-one methanesulfonic acid esterwere obtained, which was used in the next reaction step without anyfurther purification.

(b) 8.5 g (0.03 mol) of the mesylate obtained in (a) were heated at 150°C. for 3 hours with a solution of 10 g of dimethylamine in 60 ml ofdioxane in an autoclave. After cooling, the reaction mixture wasevaporated to dryness in vacuo. The residue was dissolved in 2 Nhydrochloric acid, and the solution was extracted with ether. The acidicaqueous phase was made alkaline with concentrated ammonia and thenextracted with methylene chloride. The methylene chloride phase wasdried and evaporated. The residue (6.5 g) was converted into the acidfumarate of the title compound with an equivalent amount of fumaricacid. Yield: 6.4 g (61% of theory); m.p. 137-138° C.

Using a procedure analogous to that described in Example 25, thecompounds of the formula I shown in the folliwing table were alsoprepared:

                                      TABLE II                                    __________________________________________________________________________     ##STR30##                                                                    Example                                                                       No.  R          R.sub.1                                                                         R.sub.2    Mp.                                                                              °C./Bp. °C.                     __________________________________________________________________________    26   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR31## Mp.                                                                              163-164 (Hydrochloride)                       27                                                                                  ##STR32## H                                                                                ##STR33## Mp.                                                                              167-169 (Oxalate)                             28                                                                                  ##STR34## H                                                                                ##STR35## Mp.                                                                              258 (Dihydrochloride)                         29                                                                                  ##STR36## H                                                                                ##STR37## Mp.                                                                              188-190 (Hydrochloride)                       30   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR38## Mp.                                                                              163-164 (Fumarate)                            31   N(C.sub.2 H.sub.5 ).sub.2                                                                H                                                                                ##STR39## Mp.                                                                              152-153 (Hydrochloride)                       32   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR40## Mp.                                                                              157-158 (Fumarate)                            33   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR41## Mp.                                                                              149-151 (Hydrochloride)                       34   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR42## Mp.                                                                              167-168 (Fumarate)                            35   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR43## Mp.                                                                              159-161 (Hydrochloride)                       36   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR44##    Oil (Base)                                    37   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR45##    Oil (Base)                                    __________________________________________________________________________

Example 38 1-Benzyl-5-aminomethyl-pyrrolidin-2-one 6.4 g (0.07 mol) of1-benzyl-5-hydroxymethyl-pyrrolidin-2-one methanesulfonic acid ester[see Example 25(a)]were dissolved in 200 ml of dimethylformamide, andthe solution was stirred for 90 minutes at 100° C. after the addition of4.6 g (0.07 mol) of sodium azide. After evaporation of the reactionmixture, taking up the residue in a mixture of water and methylenechloride, and working up of the organic phase, 13.8 g (92% of theory) ofan oil were obtained, which was reacted further in its crude form. Itwas dissolved in 200 ml of methanol, and after the addition of Raneynickel the solution was hydrogenated at 20° C. and 5 bar. After thecatalyst had been removed by suction filtration and the filtrate hadbeen evaporated, 11 g (85% of theory) of an oil were obtained which,when dissolved in methanol and after the addition of fumaric acid,yielded the desired hemifumarate of the title compound (m.p. 187-188°C.).

The compounds of the present invention, that is, those embraced byformula I, as well as1-(α-methyl-benzyl)-5-aminomethyl-pyrrolidin-2-one, have usefulpharmacodynamic properties. More particularly, they exhibit nootropicactivity in warm-blooded animals, that is, they alleviate or cureconditions of impaired functional capacity of the brain.

The above pyrrolidinone derivatives were tested in animal experimentswith regard to their activity of curing or alleviating conditions ofimpaired cerebral performance.

In tolerance tests, which were carried out as a guide, the compoundsshow no acute toxicity (14 days observation) when administered to micein doses of up to 2 g/kg (single oral administration). In animalexperiments they show excellent effects on spontaneous cognitiveperformance, such as experimentally impaired learning and memoryprocesses. In tests with a restriction of the short term memory orinhibition of the transition from contents of the short term memory tothe long term memory, by the administration of a muscarinic cholinergicantagonist [scopolamine 0.6 mg/kg i.p.; see also Psychopharmacology 78,104-111 (1982)], the compounds are capable of counteracting or evencuring this pharmacologically induced cerebral insufficiency.

The learning capacities of rats in an active avoidance training [J.Pharmacol. Methods, 8, 155-163 (1983)]are improved as is theirspontaneous habituation or exploring orientation activity in a newenvironment.

The pyrrolidinone derivatives were compared in their activity withpyrrolidinones of different structures which are already used as drugsin human medicine (piracetam) or are at present undergoing clinicaltrials (anirazetam) with regard to cerebral insufficiency or organicbrain psychodrome, posttraumatic and alcoholic brain damage, etc.

In tests to determine the survival of animals in a closed chamber(hypoxia tolerance test) through which a gas mixture consisting of 96.5%N₂ and 3.5% O₂ was passed, the animals pretreated with the pyrrolidinonederivatives had a statistically highly significantly greater survivalrate than control animals or animals pre-treated with piracetam.Moreover, the brainprotecting activity of the substances tested by thismethod was very marked even at a dosage of 50 mg/kg p.o.

The pyrrolidinone derivatives are clearly superior to theabove-mentioned pyrrolidinones of different structures, both in theireffective dosage and also in the improvement in performance obtained inthe animal experiments.

For pharmaceutical purposes the pyrrolidinone derivatives areadministered to warm-blooded animals perorally or parenterally as activeingredients in customary pharmaceutical compositions, that is,compositions consisting essentially of an inert pharmaceutical carrierand an effective amount of the active ingredient, such as tablets,coated pills, capsules, wafers, powders, solutions, suspensions,emulsions, syrups and the like. An effective amount of the compoundsaccording to the present invention is from 0.7 to 2.8 mg/kg body weight,preferably 1.0 to 2.1 mg/kg body weight.

The novel compounds may be used either by themselves or in combinationwith other active substances of the instant invention, possibly togetherwith other pharmacologically active substances, such as othercerebro-activators.

Suitable tablets may be prepared, for example, by mixing the or eachactive substance with known excipients, for instance with inert diluentssuch as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as corn starch or alginic acid, binders such as starch or gelatin,lubricants such as magnesium stearate or talc, and/or agents forobtaining delayed release such as carboxypolymethylene,carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate.The tablets may also consist of several layers.

Coated tablets may be produced similarly by coating cores producedanalogously to the tablets with agents conventionally used in tabletcoatings, such as collidone or shellac, gum arabic, talc, titanium oxideor sugar. In order to achieve delayed release or avoidincompatibilities, the core may also consist of several layers.Similarly, the tablet coating may be made up of a number of layers inorder to obtain delayed release, and the excipients mentioned for thetablets may be used.

Syrups of the active substances or combinations of active substancesaccording to the invention may additionally contain a sweetener such assaccharin, cyclamate, glycerol or sugar and a flavor-improving agent,for instance a flavoring such as vanillin or orange extract. They mayalso contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, for example condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Injection solutions are prepared in the conventional way, for instanceby adding preservatives such as p-hydroxybenzoates or stabilizers suchas alkali metal salts of ethylene diamine tetraacetic acid, and thesesolutions are then transferred into injection vials or ampules.

Capsules containing one or more active substances or combinations ofactive substances may be prepared, for example, by mixing the activesubstances with inert carriers such as lactose or sorbitol and fillinggelatin capsules therewith.

Suitable suppositories may be produced, for example, by mixing withcarriers provided for this purpose such as neutral fats or polyethyleneglycol or derivatives thereof.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of using the invention. Theparts are parts by weight unless otherwise specified.

EXAMPLE 39 Tablets

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        1-Benzyl-4-aminomethyl-pyrrolidin-2-one                                                               100 parts                                             Lactose (powdered)      140 parts                                             Corn starch             240 parts                                             Polyvinyl pyrrolidone    15 parts                                             Magnesium stearate       5 parts                                                                      500 parts                                             ______________________________________                                    

Preparation:

The finely ground active ingredient, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinyl pyrrolidone in water, kneaded, moist-granulatedand dried. The granulate, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed into500 mg-tablets of a suitable size and shape, each of which contains 100mg of the active ingredient.

EXAMPLE 40 Tablets

The tablet compositions is compounded from the following ingredients:

    ______________________________________                                        1-(p-Fluorobenzyl)-4-aminomethyl-                                                                   80 parts                                                pyrrolidin-2-one                                                              Corn starch           190 parts                                               Lactose               55 parts                                                Microcrystalline cellulose                                                                          35 parts                                                Polyvinyl pyrrolidone 15 parts                                                Sodium carboxymethyl starch                                                                         23 parts                                                Magnesium stearate     2 parts                                                                      400 parts                                               ______________________________________                                    

Preparation:

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinyl pyrrolidone are mixed together,the mixture is screened and processed with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added, and themixture is compressed into 400 mg-tablets of a suitable size and shape,each of which contains 80 mg of the active ingredient.

EXAMPLE 41 Injectable Solution

    ______________________________________                                        1-(p-Fluorobenzyl)-4-aminomethyl-                                                                    50 parts                                               pyrrolidin-2-one fumarate                                                     Sodium chloride        10 parts                                               Double-distilled water q.s. ad                                                                      1000 parts by vol.                                      ______________________________________                                    

Preparation:

The active ingredient and the sodium-chloride are dissolved in asufficient quantity of double-distilled water, and the solution isdiluted to the desired concentration with the required amount ofdouble-distilled water. The solution is filtered and filled into 1ml-ampules under aseptic conditions Finally, the ampules are sterilizedand sealed. Each ampule contains 80 mg of the active ingredient.

EXAMPLE 42 Drop Solution

The solution is compounded from the following

    ______________________________________                                        1-(4-Fluorobenzyl)-4-aminomethyl-                                                                    5.0 parts                                              pyrrolidin-2-one fumarate                                                     Methyl p-hydroxybenzoate                                                                             0.1 parts                                              Propyl p-hydroxybenzoate                                                                             0.1 parts                                              Demineralized water q.s. ad                                                                         100.0 parts by vol.                                     ______________________________________                                    

Preparation:

The active ingredient and the p-hydroxybenzoates are dissolved in thedemineralized water, the solution is filtered, and the filtrate isfilled into 100 ml-bottles equipped with a dropping spout. Each bottlecontains 5 g of.the active ingredient.

Any one of the other compounds embraced by formula I, or1-(α-methyl-benzyl)-5-aminomethyl-pyrrolidin-2-one, or a non-toxic,pharmacologically acceptable acid addition salt thereof, may besubstituted for the particular active ingredient in Examples 39 through42. Likewise, the amount of active ingredient in these illustrativeexamples may be varied to achieve the dosage unit range set forth above,and the amounts and nature of the inert pharmaceutical carrieringredients may be varied to meet particular requirements.

While the present invention has been illustrated with, the aid ofcertain specific embodiments thereof, it will be readily apparent toothers skilled in the art that the invention is not limited to theseparticular embodiments, and that various changes and modifications maybe made without departing from the spirit of the invention or the scopeof the appended claims.

We claim:
 1. A compound of the formula ##STR46## wherein R₁ is hydrogenor alkyl of 1 to 4 carbon atoms; andR₂ is phenyl or mono- ordi-substituted phynyl, where the substituents are each individuallyalkoxy of 1 to carbon atoms, fluorine, chlorine, bromine,trifluoromethyl, alkyl or 1 to 4 carbon atoms, hydroxyl or nitro;wherethe pyrrolidinomethyl substituent is attached to the 4- or 5position ofthe pyrrolidien ring, or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 2. A compound of claim 1, which is1-benzyl-5-(pyrrolidinylmethyl)-pyrrolidin-2one or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 3. A nootropicpharmaceutical composition consisting essentially of an inertpharmaceutical carrier and an effecte nootropic amount of a compound ofthe formula ##STR47## wherein R₁ is hydrogen or alkyl of 1 to 4 carbonatoms; andR₂ is phynyl or mono- or di-substituted phenyl, where thesubstituents are each individually alkoxy of 1 to 2 carbon atoms,fluorine, chlorien, bromine, trifluoromethyl, alkyl of 1 4 carbon atoms,hydroxyl or nitro;where the pyrrolidinomethyl substituent is attached tothe 4- or 5position of the pyrrolidine ring, or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 4. A nootropicpharmaceutical composition of claim 3, wherein said compoun is1benzyl-5-(pyrrolidinylmethyl)-pyrrolidin-2-one or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 5. The methodof alleviating conditions of impaired cerebral performance in awarm-blooded animal in need therof, which comprises perorally orparenterally administering to said animal an effective nootropic amountof a compound of the formula ##STR48## wherein R₁ is hydrogen or alkylof 1 to 4 carbon atoms; andR₂ is phynyl or mono- or di-substitutedphenyl, where the substituents are each individually alkoxy of 1 or 2carbon atoms, fluorine, chlorien, bromine, trifluormethyl, alkyl of 1 to4 carbon atoms, hydroxyl or nitro; where the pyrrolidinomethylsubstituent is attached to the 4- or 5-position of the pyrrolidien ring,or a non-toxic, pharmacologically acceptable acid addition salt thereof.6. The mthod of cliam 5, wherein said ocmpound is1-benzyl-5-(pyrrolidinylmethyl)-pyrrolidin-2-one or a non-toxic,pharmacologically acceptable acid addition salt thereof.